Process for preparing 5-&#39;(r)-2-(5,6-diethyl-indian-2-ylamino)-1-hydroxy-ethyl!-8-hydroxy-(1h)-quinolin-2-one salt, useful as an andrenoceptor agonist

ABSTRACT

A process for preparing 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-one salt. The process involves forming an acid salt of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-substituted oxy-(1H)-quinolin-2-one; and converting the acid salt to a salt of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-one without isolating the free base of 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-one.

The present invention provides a process for preparing5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt without isolating the free base thereof which is unstable inorganic solvents.

5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolinone-2-one salts are β-selective adrenoceptor agonists withpotent bronchodilator activity. For example,5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolinone-2-onemaleate is especially useful for treating asthma and COPD. In addition,the maleate salt has been shown to have a very long duration of actionin vitro and in vivo.

In a process for preparing5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolinone-2-onemaleate, an epoxide, such as 8-substitutedoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one [Formula (I)], is reacted with anamine, such as 2-amino-(5-6-diethyl)-indan, to form a desiredintermediate5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-substitutedoxy-(1H)-quinolin-2-one [Formula (II)]. However, the reaction is notregioselective and delivers various amounts of a regioisomer [Formula(III)] and a dimer [Formula (IV)].

Generally, the reaction mixture above contains only about 60% to 80% ofthe desired intermediate having Formula (II). In addition, it isdifficult to purify the intermediate having Formula (II) bycrystallization without a high loss of yield. For example, silica gelchromatography has been used for such a purification, however, scale-upof silica gel chromatography is tedious and requires large volumes ofsolvents.

It would be desirable to develop a more efficient process for preparing5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolinone-2-onesalts especially for large scale production, which provides the salts inhigh enantiomeric purity and high yield.

The invention provides a process for preparing5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt or an acceptable solvate thereof comprising:

(i) reacting 8-substituted oxy-5-(R)-oxiranyl-(1H)-quinolin-2-one havingFormula (I)

-   -   with 2-amino-(5-6-diethyl)-indan to form a reaction mixture        containing compounds having Formulae (II), (III) and (IV)    -   wherein R is a protecting group;

(ii) treating the reaction mixture prepared in Step (i) with an acid inthe presence of a solvent to form a corresponding salt;

(iii) isolating and crystallizing a salt having Formula (V)

-   -   wherein R is a protecting group and A- is an anion;

(iv) removing the protecting group from the salt having Formula (V) inthe presence of a solvent to form a salt having Formula (VI):

-   -   wherein A- is an anion; and

(v) treating the salt having Formula (VI) with an acid in the presenceof a solvent to form5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt having Formula (VII)

-   -   wherein X— is an anion.

Terms used in the specification have the following meanings:

As used herein, “alkyl” means straight chain or branched alkyl, whichmay be, e.g,, C₁-C₁₀alkyl, such as methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, straight- or branched-pentyl,straight- or branched-hexyl, straight- or branched-heptyl, straight- orbranched-nonyl or straight- or branched-decyl. Preferably alkyl isC₁-C₄alkyl.

“Aryl” means C₆-C₁₄aryl, preferably C₆-C₁₀aryl, and may be, e.g.,substituted by at least one group selected from mercapto, dialkylamino,nitro, alkoxy, halogen, keto, cyano or a combination. Preferably aryl isphenyl.

“Alkoxy” means straight chain or branched alkoxy and may be, e.g.,C₁-C₁₀alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy or straight- or branched-pentoxy,-hexyloxy, -heptyloxy, -octyloxy, -nonyloxy or -decyloxy. Preferablyalkoxy is C₁-C₄alkoxy.

“Alkenyl” means straight chain or branched-alkenyl, which may be, e.g.,C₂-C₁₀alkenyl, such as vinyl, 1-propenyl, 2-propenyl, 1-butenyl,isobutenyl, or straight- or branched-pentenyl, -hexenyl, -heptenyl,-octenyl, -nonenyl or -decenyl. Preferred alkenyl is C₂-C₄alkenyl.“Cycloalkyl” means C₃-C₁₀cycloalkyl having 3- to 8-ring carbon atoms andmay be, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cycloheptyl, any of which can be substituted by one, twoor more C₁-C₄alkyl groups, particularly methyl groups. Preferably,cycloalkyl is C₃-C₆cycloalkyl.

“Benzocycloalkyl” means cycloalkyl, e.g., one of the C₃-C₁₀cycloalkylgroups mentioned hereinbefore, attached at two adjacent carbon atoms toa benzene ring. Preferably, benzocycloalkyl is benzo-C₅-C₆cycloalkyl,especially, benzocyclohexyl (tetrahydronaphthyl).

“Cycloalkylalkyl” means C₃-C₁₀cycloalkylC₁-C₁₀alkyl, where theC₃-C₁₀cycloalkyl group has 3- to 8-ring carbon atoms and may be, e.g.,one of the C₁-C₁₀alkyl groups mentioned hereinbefore, particularly oneof the C₁-C₄alkyl groups, substituted by one of the C₃-C₁₀cycloalkylgroups mentioned hereinbefore. Preferably cycloalkylalkyl isC₃-C₆cycloalkylC₁-C₄alkyl.

“Aralkyl” means straight-chain or branched-C₆-C₁₀arylC₁-C₁₀alkyl and maybe, e.g., one of the C₁-C₁₀alkyl groups mentioned hereinbefore,particularly one of the C₁-C₄alkyl groups, substituted by phenyl, tolyl,xylyl or naphthyl. Preferably, aralkyl is phenylC₁-C₄alkyl, particularlybenzyl or 2-phenylethyl.

“Heterocyclic” means a monovalent heterocyclic group having up to 20carbon atoms and one, two, three or four heteroatoms selected fromnitrogen, oxygen and sulfur, the group optionally having an alkyl,alkylcarbonyl, hydroxyalkyl, alkoxyalkyl or aralkyl group attached to aring carbon or nitrogen atom and being linked to the remainder of themolecule through a ring carbon atom, and may be, e.g., a group,preferably a monocyclic group, with one nitrogen, oxygen or sulfur atom,such as pyrryl, pyridyl, piperidyl, furyl, tetrahydrofuryl or thienyl,or a group, preferably a monocyclic group, with two hetero atomsselected from nitrogen, oxygen and sulfur, such as imidazolyl,pyrimidinyl, piperazinyl, oxazolyl, isoxazolyl, thiazolyl, morpholinylor thiomorpholinyl. Preferably, heterocyclic is a monocyclic grouphaving 5- or 6-ring atoms and one or two nitrogen atoms, or one nitrogenatom and one oxygen atom, in the ring and optionally substituted on aring nitrogen atom by C₁-C₄alkyl, hydroxyC₁-C₄alkyl, C₁-C₄alkylcarbonylor phenylC₁-C₄alkyl.

“Heteroaralkyl” means straight-chain or branched-aralkyl, e.g., one ofthe C₆-C₁₀arylC₁-C₁₀alkyl groups mentioned hereinbefore, substituted byone or more heterocyclic groups.

“Haloalkyl” means straight-chain or branched-alkyl, e.g., C₁-C₁₀alkyl,such as one of the C₁-C₁₀alkyl groups mentioned hereinbefore,substituted by one or more, e.g., one, two or three, halogen atoms,preferably fluorine or chlorine atoms. Preferably haloalkyl isC₁-C₄alkyl substituted by one, two or three fluorine or chlorine atoms.

“Substituted silyl group” is preferably a silyl group substituted withat least one alkyl group as herein defined.

In a second aspect the invention provides a process for preparing5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt or an acceptable solvate thereof comprising:

(a) reacting an 8-(substituted oxy)-5-haloacetyl-(1H)-quinolin-2-onewith a reducing agent in the presence of a chiral catalyst to form8-(substituted oxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one;

(b) treating the 8-(substitutedoxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one with a base inthe presence of a solvent to form 8-(substitutedoxy)-5-(R)-oxiranyl-(1H)-quinolin-2-one;

(c) reacting the 8-substituted oxy-5-(R)-oxiranyl-(1H)-quinolin-2-onehaving Formula (I)

-   -   with 2-amino-(5-6-diethyl)-indan to form a reaction mixture        containing compounds having Formulae (II), (III) and (IV)    -   wherein R is a protecting group;

(d) treating the reaction mixture prepared in Step (i) with an acid inthe presence of a solvent to form a corresponding salt;

(e) isolating and crystallizing a salt having Formula (V)

-   -   wherein R is a protecting group and A- is an anion;

(f) removing the protecting group from the salt having Formula (V) inthe presence of a solvent to form a salt having Formula (VI):

-   -   wherein A- is an anion; and

(g) treating the salt having Formula (VI) with an acid in the presenceof a solvent to form5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt having Formula (VII)

-   -   wherein X— is an anion.

The present invention provides a process for preparing5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt or an acceptable solvate thereof.

In the first step, Step (i), 8-substitutedoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one having Formula (I)

is reacted with 2-amino-(5-6-diethyl)-indan to form a reaction mixturecontaining compounds having Formulae (II), (III) and (IV):

wherein R is a protecting group.

Preferred protecting groups are phenol protecting groups which are knownto those skilled in the art. More preferably, the protecting group isselected from the group consisting of an alkyl, aryl, alkoxy, alkenyl,cycloalkyl, benzocycloalkyl, cycloalkylalkyl, aralkyl, heterocyclic,heteroaralkyl, haloalkyl, and a substituted silyl group. Mostpreferably, the protecting group is benzyl or t-butyldimethylsilyl.

Preferably, Step (i) is conducted in the presence of a solvent.Preferred solvents include: alcohols, e.g., C₁₋₆alkyl alcohols, such asmethanol, ethanol, propanol, butanol, and pentanol; aliphaticC₆₋₁₂hydrocarbons, e.g., isooctane, heptane;dimethylformamide; aromatichydrocarbons, such as toluene and benzene; acetonitrile; heterocycles,such as tetrahydrofuran; dialkyl ethers, e.g., diisopropyl ether,2-methoxyethyl ether and diethylene ether; dimethyl sulfoxide;tetrahydrothiophene 1,1-dioxide, also known as tetramethylene sulfone oras tetramethylene sulfolane; dialkyl carbonate, e.g., dimethyl carbonateand diethyl carbonate; aqueous solvents, such as water; ionic liquids;and chlorinated solvents, such as methylenechloride. A combination ofsolvents may also be used. More preferably, the solvent is2-methoxyethyl ether or butanol.

The temperature used in Step (i) is preferably from about 10° C. toabout 160° C. More preferably, the temperature is from about 30° C. toabout 120° C.; and most preferably from about 90° C. to about 120° C.

Preferably, Step (i) is conducted with a molar excess of the2-amino-(5-6-diethyl)-indan with respect to the 8-substitutedoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one. Preferably, 1.05 mole equivalentto 3 mole equivalents of 2-amino-(5-6-diethyl)-indan is used withrespect to 8-substituted oxy-5-(R)-oxiranyl-(1H)-quinolin-2-one. Mostpreferably, 1.1 mole equivalents to 1.5 mole equivalents of2-amino-(5-6-diethyl)-indan is used with respect to 8-substitutedoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one.

The 8-substituted oxy-5-(R)-oxiranyl-(1H-quinolin-2-one is preferably8-phenylmethoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one. The5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-substitutedoxy-(1H)-quinolin-2-one is preferably 5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-phenylmethoxy-(1H)-quinolin-2-one.

The 8-substituted oxy-5-(R)-oxiranyl-(1H)-quinolin-2-one may be preparedby reacting an 8-(substituted oxy)-5-haloacetyl-(1H)-quinolin-2-one witha reducing agent in the presence of a chiral catalyst to form8-(substituted oxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one;and treating the 8-(substitutedoxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one with a base inthe presence of a solvent to form 8-(substitutedoxy)-5-(R)-oxiranyl-(1H)-quinolin-2-one. This is described in greaterdetail below.

In the second step, Step (ii), the reaction mixture prepared in Step (i)is treated with an acid in the presence of a solvent to form acorresponding salt.

Preferred solvents for use in Step (ii) include: alcohols, e.g.,C₁₋₆alkyl alcohols, such as methanol, ethanol, propanol, butanol, andpentanol; aliphatic C₆₋₁₂hydrocarbons, e.g., isooctane, heptane;dimethylformamide; aromatic hydrocarbons, such as toluene and benzene;acetonitrile; heterocycles, such as tetrahydrofuran; dialkyl ethers,e.g., diisopropyl ether, 2-methoxyethyl ether and diethylene ether;dimethyl sulfoxide; tetrahydrothiophene 1,1-dioxide, also known astetramethylene sulfone or as tetramethylene sulfolane; dialkylcarbonate, e.g., dimethyl carbonate and diethyl carbonate; aqueoussolvents, such as water; ionic liquids; and chlorinated solvents, suchas methylenechloride. A combination of solvents may also be used. Morepreferably, the solvent is ethanol. The temperature used in Step (ii) ispreferably from about −10° C. to about 160° C. More preferably, thetemperature is from about 0° C. to about 120° C.; and most preferablyfrom about 0° C. to about 75° C.

In the third step, Step (iii), a salt having Formula (V)

is isolated and crystallized, wherein R is a protecting group; and A- isan anion. The anion corresponds to the acid used in Step (ii). The acidused in Step (ii) is preferably a carboxylic acid, such as benzoic acid,maleic acid, succinic acid, fumaric acid, or tartaric acid; or a mineralacid, such as hydrochloric acid. Most preferably, the acid used in Step(ii) is benzoic acid.

The salt having Formula (V) is preferably a benzoate salt having Formula(VIII)

wherein R is a protecting group.

More preferably, the benzoate salt having Formula (VIII) is a benzoatesalt having Formula (IX)

In the fourth step, Step (iv), the protecting group on the salt havingFormula (V) is removed in the presence of a solvent to form a salthaving Formula (VI)

wherein A- is an anion.

The salt having Formula (VI) is preferably a benzoate salt havingFormula (X)

The removal of a protecting group is known to those skilled in the artand depends on the type of protecting group. In one embodiment where theprotecting group is benzyl, a preferred method of removing the benzylgroup on the salt having Formula (V) is by treating the salt withhydrogen in the presence of a catalyst. Preferred catalysts includepalladium, palladium hydroxide, palladium on activated carbon, palladiumon alumina, palladium on carbon powder, platinum, platinum on activatedcarbon and Raneyl nickel. A combination of catalysts may also be used.Most preferably, the catalyst is palladium on activated carbon.

In one embodiment where the protecting group is t-butyldimethylsilyl, apreferred method of removing the t-butyldimethylsilyl group on the salthaving Formula (V) is by treating the salt with t-butylammonium fluorideor potassium fluoride.

The solvent used in Step (iv) is preferably selected from an alkylacetate, e.g., C₁₋₆alkyl acetates, such as ethyl acetate, isopropylacetate and butyl acetate; lower alkyl alkylamines, e.g.,C₁₋₆alkylamines; alcohols, e.g., C₁₋₆alkyl alcohols, such as methanol,ethanol, propanol, butanol and pentanol; aliphatic C₆₋₁₂hydrocarbons,e.g., isooctane, heptane, dimethylformamide; aromatic hydrocarbons, suchas toluene and benzene; acetonitrile; heterocycles, such astetrahydrofuran; dialkyl ethers, e.g., diisopropyl ether, 2-methoxyethylether, and diethylene ether; an acid, e.g., acetic acid, trifluoroaceticacid, and propionic acid; aqueous solvents, such as water; ionicliquids; and chlorinated solvents, such as methylenechloride. Acombination of solvents may also be used. More preferably, the solventis acetic acid or 2-propanol.

The temperature used in Step (iv) is preferably from about 0° C. toabout 70° C. More preferably, the temperature is from about 10° C. toabout 50° C.; and most preferably from about 10° C. to about 30° C.

The salt having Formula (VI) is preferably5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onebenzoate.

In the fifth step, Step (v), the salt having Formula (VI) is treatedwith an acid in the presence of a solvent to form a salt having Formula(VII)

wherein X— is an anion. The anion corresponds to the acid used in Step(v). The acid used in Step (v) is preferably a carboxylic acid, such asbenzoic acid, maleic acid, succinic acid, fumaric acid, or tartaricacid. Most preferably, the acid used in Step (v) is maleic acid.

The salt having Formula (VII) is isolated, preferably by filtration. Thesalt having Formula (VII) is preferably5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onemaleate having Formula (XI):

The solvent used in Step (v) is preferably selected from an alkylacetate, e.g., C₁₋₆alkyl acetates, such as ethyl acetate, isopropylacetate and butyl acetate; alcohols, e.g., C₁₋₆alkyl alcohols, such asmethanol, ethanol, propanol, isopropanol, butanol and pentanol;dimethylformamide; aromatic hydrocarbons, such as toluene and benzene;dialkyl ketones, e.g., acetone and methyl isobutyl ketone; acetonitrile;heterocycles, such as tetrahydrofuran; dialkyl ethers, e.g., diisopropylether, 2-methoxyethyl ether and diethylene ether; an acid such as aceticacid and propionic acid; aqueous solvents, such as water; ionic liquids;and chlorinated solvents, such as methylenechloride. A combination ofsolvents may also be used. More preferably, the solvent is ethanol.

The temperature used in Step (v) is preferably from about 0° C. to about70° C. More preferably, the temperature is from about 10° C. to about60° C.; and most preferably from about 20° C. to about 50° C.

As mentioned above, the 8-substitutedoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one may be prepared by (a) reactingan 8-(substituted oxy)-5-haloacetyl-(1H)-quinolin-2-one with a reducingagent in the presence of a chiral catalyst to form 8-(substitutedoxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one; and then (b)treating the 8-(substitutedoxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one with a base inthe presence of a solvent to form 8-(substitutedoxy)-5-(R)-oxiranyl-(1H)-quinolin-2-one.

For example, in Step (a), the 8-substitutedoxy-5-haloacetyl-(1H)-quinolin-2-one is reacted with a reducing agent inthe presence of a chiral catalyst to form a 8-substitutedoxy-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one of Formula (XII):

wherein R is a protecting group; and X is a halogen. The halogen isselected from bromine, chlorine, fluorine and iodine. Preferably, thehalogen is chlorine.

The 8-substituted oxy-5-haloacetyl-(1H)-quinolin-2-one is commerciallyavailable or may be prepared by halogenating the correspondingmethylketone, for example using the procedure described in internationalpatent application WO 95/25104. The methylketone is commerciallyavailable or may be prepared using the procedure described in EuropeanJournal of Medicinal Chemistry, 1984, 19, 341-346.

Preferably, the chiral catalyst is an oxazaborolidine compound ofFormula (XIII):

wherein R^(a) and R^(b) are, independently, selected from an aliphatic,cycloaliphatic, cycloaliphatic-aliphatic, aryl or aryl-aliphaticresidue. Preferably, R^(a) and R^(b) are, independently, selected fromphenyl, 4-methylphenyl, and 3,5-dimethylphenyl. More preferably, R^(a)and R^(b) are phenyl, and

R^(c) is selected from aliphatic, cycloaliphatic,cycloaliphatic-aliphatic, aryl or aryl-aliphatic residue, which, in eachcase, may be linked to a polymer. More preferably, R^(c) is methyl.

R^(a), R^(b) and R^(c) are preferably unsubstituted but may besubstituted, example, by one or more, e.g., two or three, residues,e.g., those selected from C₁-C₇ alkyl, hydroxy, —O—CH₂—O—, —CHO, C₁-C₇substituted oxy, C₂-C₈ alkanoyl-oxy, halogen, e.g., chlorine orfluorine, nitro, cyano and CF₃.

Aliphatic hydrocarbon residues include C₁-C₇ alkyl, C₂-C₇ alkenyl orsecondarily C₂-C₇ alkynyl. C₂-C₇ Alkenyl is, in particular, C₃-C₇alkenyl and is, e.g., 2-propenyl or 1-, 2- or 3-butenyl. C₃-C₅ Alkenylis preferred. C₂-C₇ Alkynyl is, in particular, C₃-C₇ alkynyl and ispreferably propylnyl.

Cycloaliphatic residues include C₃-C₈ cycloalkyl or, secondarily, C₃-C₅cycloalkenyl. C₃-C₅ cycloalkyl is preferably cyclopentyl or cyclohexyl.C₃-C₈ cycloalkenyl is C₃-C₇ cycloalkenyl is preferably cyclopent-2-en-yland cyclopent-3-enyl, or cyclohex-2-en-yl and cyclohex-3-en-yl.

Cycloaliphatic-aliphatic residues include C₃-C₅ cycloalkyl-C₁-C₇ alkyl,preferably C₃-C₆ cycloalkyl-C₁-C₄ alkyl, but especiallycyclopropylmethyl.

The aryl residue may be, for example, a carbocyclic or heterocyclicaromatic residue, in particular, phenyl or, in particular, anappropriate 5- or 6-membered and mono or multicyclic residue which hasup to four identical or different hetero atoms, such as nitrogen, oxygenor sulfur atoms, preferably one, two, three or four nitrogen atoms, anoxygen atom or a sulfur atom. Suitable 5-membered heteroaryl residuesinclude monoaza-, diaza-, triaza-, tetraaza-, monooxa- ormonothia-cyclic aryl radicals, such as pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, furyl and thienyl, while suitable appropriate6-membered residues are, in particular, pyridyl. Appropriate multicyclicresidues are anthracenyl, phenanthryl, benzo[1,3]-dioxole or pyrenyl. Anaryl residue may be mono-substituted by, e.g., NH₂, OH, SO₃H, CHO ordi-substituted by OH or CHO and SO₃H.

Aryl-aliphatic residues include phenyl-C₁-C₇ alkyl, phenyl-C₂-C₇ alkenyland phenyl-C₂-C₇ alkynyl.

Suitable polymers include polystyrene (PS), cross-linked PS (J),polyethylene glycol (PEG) or a silica gel residue (Si). Examples areNH—R^(d), wherein R^(d) is C(O)(CH₂)_(n)—PS or C(O)NH(CH₂)_(n)—PS; and—O—Si(R^(e))₂(CH₂)_(n)R^(f), wherein n is 1-7, R^(e) is C₁-C₆ alkyl,e.g., ethyl, and R^(f) is a polystyrene, cross-linked polystryrene,polyethylene glycol or a silica gel residue.

The reducing agent that is used to reduce the 8-(substitutedoxy)-5-haloacetyl-(1H)-quinolin-2-one is preferably a borane reagentsuch as borane-tetrahydrofuran complex, a borane-N,N-diethylanilinecomplex or a borane-methyl sulfide complex. A borane-tetrahydrofurancomplex is especially preferred. The oxazaborolidine chiral catalyst ispreferably(R)-tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]-oxazaborole,also known as (R)-2-methyl-CBS-oxazaborolidine (Me-CBS).

Preferably a solvent is used in Step (a). Preferred solvents include: analkyl acetate, e.g., C₁₋₆ alkyl acetates, such as ethyl acetate,isopropyl acetate and butyl acetate; alkylamines, e.g., C₁₋₆alkylamines;lower alkyl alcohols, e.g., C₁₋₆alkyl alcohols, such as methanol,ethanol, propanol, isopropanol, butanol, and pentanol; aliphatic C₆₋₁₂hydrocarbons, e.g., isooctane, heptane; dimethylformamide; aromatichydrocarbons, such as toluene and benzene; acetonitrile; heterocycles,such as tetrahydrofuran; dialkyl ethers, e.g., diisopropyl ether,2-methoxyethyl ether, and diethylene ether; aqueous solvents, such aswater; ionic liquids; and chlorinated solvents, such asmethylenechloride. A combination of solvents may also be used. Thepreferred solvent for use in Step (a) is tetrahydrofuran.

The temperature used in Step (a) is preferably from about −10° C. toabout 80° C. More preferably, the temperature is from about 0° C. toabout 50° C.

The 8-substituted oxy-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-oneis preferably8-phenylmethoxy-5-((R)-2-chloro-1-hydroxy-ethyl)-(1H)-quinolin-2-one.

Optionally, the 8-substitutedoxy-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one product may bepurified by any of the various techniques known to the art, such as bycrystallization, and may, optionally, be conducted in the presence ofcharcoal.

In the Step (b), the 8-substitutedoxy-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one is treated with abase in the presence of a solvent to form 8-substitutedoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one. The 8-substitutedoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one has Formula (I):

wherein R is a protecting group.

Preferred bases include sodium ethoxide, sodium hydroxide, potassiumphosphate, potassium carbonate, potassium hydrogencarbonate and caesiumcarbonate. A combination of bases may also be used. The base is mostpreferably potassium carbonate.

The solvent used in Step (b) is preferably selected from an alkylacetate, e.g., C₁₋₆ alkyl acetates, such as ethyl acetate, isopropylacetate and butyl acetate; alcohols, e.g., C₁₋₆alkyl alcohols, such asmethanol, ethanol, propanol, butanol, and pentanol; aliphatic C₆₋₁₂hydrocarbons, e.g., isooctane, heptane; dimethylformamide; aromatichydrocarbons, such as toluene and benzene; dialkyl ketones, e.g.,acetone, methyl isobutyl ketone; acetonitrile; heterocycles, such astetrahydrofuran; dialkyl ethers, e.g., diisopropyl ether, 2-methoxyethylether, and diethylene ether; aqueous solvents, such as water; ionicliquids; and chlorinated solvents such as methylenechloride. Acombination of solvents may also be used. A preferred solvent for use inStep (b) is a combination of acetone and water.

The temperature used in Step (b) is preferably from about 10° C. toabout 160° C. More preferably, the temperature is from about 30° C. toabout 80° C.; and most preferably from about 50° C. to about 60° C.

The 8-substituted oxy-5-(R)-oxiranyl-(1H)-quinolin-2-one is preferably8-phenlymethoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one.

Optionally, the 8-substituted oxy-5-(R)-oxiranyl-(1H)-quinolin-2-oneproduct may be purified by any of the various techniques known to theart, such as by crystallization.

Crystallization from toluene or acetone is especially preferred, andmay, optionally, be conducted in the presence of charcoal.

The invention is illustrated by the following Examples.

EXAMPLE 1 Preparation of5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-phenylmethoxy-(1H)-quinolin-2-onebenzoate

A 1 L, 4-necked flask equipped with a mechanical stirrer, thermometer,addition funnel and refluxing condenser was charged with 30.89 grams of2-amino-5,6-diethylindan and diethylene glycol dimethyl ether. To thissolution was added 36.4 grams of8-phenylmethoxy-5-(R)-oxiranyl-1H-quinolin-2-one. The resultingsuspension was heated to a temperature of 110° C. and stirred at thistemperature for 15 hours. The resulting brown solution was cooled to 70°C. At 70° C., 210 mL of ethanol was added followed by a solution of 30.3grams of benzoic acid in 140 mL of ethanol. The solution was cooled to45-50° C. and seeded. The suspension was cooled to 0-5° C.

The crude8-phenylmethoxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-onebenzoate was isolated by filtration and washed with 150 mL of ethanol inthree portions. The wet filter cake was purified by re-crystallizationfrom 1400 mL of ethanol, which gave 50.08 g pure8-phenlymethoxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-onebenzoate as a white crystalline powder.

EXAMPLE 2 Preparation of5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onemaleate

A 1 L hydrogenation vessel was charged with 40 grams of8-phenylmethloxy-5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-1H-quinolin-2-onebenzoate and 400 mL of acetic acid. Palladium on charcoal 5% (5.44 g)was added and the reaction mass was hydrogenated for 2-8 hours untilcomplete conversion to5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one.The mixture was filtered over a pad of filter-aid. The filtrate wasconcentrated at 50-60° C. under vacuum (100 mbar) to a volume of 70-90mL. This residue was dissolved in 400 mL of ethanol and heated to 50-60°C. A solution of 11.6 g maleic acid in 24 mL ethanol was added and theresulting clear solution was seeded at an internal temperature of 50° C.with a suspension of 350 mg micronised5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onein 20 mL isopropanol. The product was crystallized by slow cooling to0-5° C.

Filtration and washing with 50 mL of ethanol followed by 25 mL ofisopropanol provided 65 g crude5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onemaleate which was further purified by crystallization from 1.36 L ofethanol. This gave 24.3 g pure5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-onemaleate as a white crystalline powder.

EXAMPLE 3 Purity and Yield of Different Salts of5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-substitutedoxy-(1H)-quinolin-2-one

A 1 L, 4-necked flask equipped with a mechanical stirrer, thermometer,addition funnel and refluxing condenser was charged with 30.89 grams of2-amino-5,6-diethylindan and diethylene glycol dimethyl ether. To thissolution was added 36.4 grams of8-phenylmethoxy-5-(R)-oxiranyl-1H-quinolin-2-one. The resultingsuspension was heated to a temperature of 110° C. and stirred at thistemperature for 15 hours. The resulting brown solution was cooled to 70°C.

The reaction was conducted as follows:

As determined by HPLC, the reaction mixture contained 68.7% of acompound having Formula (II), 7.8% of a compound having Formula (III),and 12.4% of a compound having Formula (IV). The reaction mixture wassplit in equal portions and each portion was individually treated withan acid selected from benzoic acid, maleic acid, succinic acid, fumaricacid, tartaric acid and hydrochloric acid. The results are summarized inTable 1 as follows: TABLE 1 Salt Purity [%(Area)] Yield [%] Benzoate 9660 Maleate 98 28 Fumarate 97 48 Succinate 98 30 Tartrate 98 25Hydrochloride 87 25

As set forth in Table 1, the percent yield was based on the amount of8-substituted oxy-5-(R)-oxiranyl-(1H)-quinolin-2-one, and the purity wasbased on the salt having Formula (II) and was determined by HPLC.

Thus, it has surprisingly been found that (a) the yield of5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt may be significantly increased by forming an acid salt of5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-substitutedoxy-(1H)-quinolin-2-one; and (b) the acid salt can be converted to asalt ofS-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-²-onewithout isolating the free base of5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-one.

EXAMPLE 4 Preparation of8-(phenylmethoxy)-5-((R)-2-chloro-1-hydroxy-ethyl)-(1H)-quinolin-2-one

A dry 3 L, 4-necked flask equipped with a mechanical stirrer,thermometer, addition funnel and refluxing condenser is charged with 50g 8-(phenylmethoxy)-5-(α-chloroacetyl)-(1H)-quinolin-2-one and 600 mLdry THF under N₂. Then 15 mL of a 1 molar solrption of(R)-tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]-oxazaborolein toluene was added. The mixture was cooled to an internal temperatureof 0-2° C. and while maintaining an internal temperature of 0-2° C., 153mL of a 1 molar solution of BH₃ in THF was added over 1-2 hours. Thereaction was stirred for another hour at an internal temperature of 0-2°C. and then quenched by addition of 65 mL methanol. The resultingsolution was warmed to 25° C. and concentrated to a volume of 250 mL(50° C./200 mbar). To this concentrate was added a mixture of 713 mLwater and 37 g HCl 37%. During the addition8-(phenylmethoxy)-5-((R)-2-chloro-1-hydroxy-ethyl)-(1H)-quinolin-2-oneprecipitated as a nearly colourless precipitation. The resultingsuspension was stirred for 30 minutes at 25° C., filtrated and washedwith 220 mL water in several portions. Drying in a vacuum drier at 50°C. for 12 hours resulted in 47.41 g of8-(phenylmethoxy)-5-((R)-2-chloro-1-hydroxy-ethyl)-(1H-quinolin-2-one asa slightly yellowish powder.

EXAMPLE 5 Preparation of8-(phenylmethoxy)-5-(R)-oxiranyl-(1H)-quinolin-2-one

A 3 L, 4-necked flask equipped with a mechanical stirrer, thermometer,addition funnel and refluxing condenser was charged with 50 g8-(phenylmethoxy)-5-((R)-2-chloro-1-hydroxy-ethyl)-(1H)-quinolin-2-one,52.42 g potassium carbonate, 2500 mL acetone and 25 mL water. Themixture was heated under stirring to reflux. Refluxing was maintainedfor 5-10 hours until an in process control showed complete conversion of8-phenylmethoxy-5-((R)-2-chloro-1-hydroxy-ethyl)-(1H)-quinolin-2-one to8-phenylmethoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one. When the reactionwas completed, the hot (45-50 C) reaction mixture was filtered to removethe inorganic salts. The residue was washed with several portions ofacetone, and the combined mother liquor and acetone washings wereconcentrated to a volume of 450 mL. To the resulting suspension wasadded 235 mL heptanes at 25° C. and then the suspension was cooled to aninternal temperature of 0-2° C. and stirred at this temperature for 2-3hours. Filtration and washing resulted in a crude8-phenylmethoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one which wasre-crystallized from toluene. This resulted in 36.7 g8-(phenylmethoxy)-5-(R)-oxiranyl-(1H)-quinolin-2-one as nearlycolourless solid.

1. A process for preparing5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt or an acceptable solvate thereof comprising: (i) reacting8-substituted oxy-5-(R)-oxiranyl-(1H)-quinolin-2-one having Formula (I)

with 2-amino-(5-6-diethyl)-indan to form a reaction mixture containingcompounds having Formulae (II), (III) and (IV)

wherein R is a protecting group; (ii) treating the reaction mixtureprepared in Step (i) with an acid in the presence of a solvent to form acorresponding salt; (iii) isolating and crystallizing a salt havingFormula (V)

wherein R is a protecting group and A⁻ is an anion; (iv) removing theprotecting group from the salt having Formula (V) in the presence of asolvent to form a salt having Formula (VI):

wherein A⁻ is an anion; and (v) treating the salt having Formula (VI)with an acid in the presence of a solvent to form a5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt having Formula (VII)

wherein X⁻ is an anion.
 2. A process for preparing5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt or an acceptable solvate thereof comprising: (i) reacting8-substituted oxy-5-(R)-oxiranyl-(1H)-quinolin-2-one having Formula (I)

with 2-amino-(5-6-diethyl)-indan to form a reaction mixture containingcompounds having Formulae (II), (III) and (IV)

wherein R is a protecting group; (ii) treating the reaction mixtureprepared in Step (i) with a carboxylic acid in the presence of a solvent to form a corresponding salt, (iii) isolating and crystallizing asalt having Formula (V)

wherein R is a protecting group and A⁻ is an anion; (iv) removing theprotecting group from the salt having Formula (V) in the presence of asolvent to form a salt having Formula (VI):

wherein A⁻ is an anion; and (v) treating the salt having Formula (VI)with a carboxylic acid in the presence of a solvent to form a5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt having Formula (VII)

wherein X⁻ is an anion.
 3. A process according to claim 2, wherein thecarboxylic acid in Step (ii) and or Step (v) is selected from the groupconsisting of benzoic acid, maleic acid, succinic acid, fumaric acid,and tartaric acid.
 4. A process according to claim 3, wherein thecarboxylic acid in Step (ii) is benzoic acid.
 5. A process according toclaim 3, wherein the carboxylic acid in Step (v) is maleic acid.
 6. Aprocess according to claim 1, wherein the5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt has Formula (XI):


7. A process according to claim 1, wherein the protecting group isselected from the group consisting of an alkyl, aryl, alkoxy, alkenyl,cycloalkyl, benzocycloalkyl, cycloalkylalkyl, aralkyl, heterocyclic,heteroaralkyl, haloalkyl, and a substituted silyl group.
 8. A processaccording to claim 7, wherein the protecting group is benzyl ort-butyldimethylsilyl.
 9. A process according to claim 8, wherein theprotecting group on the salt having Formula (V) is benzyl and is removedby treating the salt with hydrogen in the presence of a catalyst.
 10. Aprocess according to claim 9, wherein the catalyst is selected from thegroup consisting of palladium, palladium hydroxide, palladium onactivated carbon, palladium on alumina, palladium on carbon powder,platinum, platinum on activated carbon, Raney™ nickel and combinationsthereof.
 11. A process according to claim 8, wherein the protectinggroup on the salt having Formula (V) is t-butyldimethylsilyl and isremoved by treating the salt with t-butylammonium fluoride or potassiumfluoride.
 12. A process according to claim 1, wherein the temperature inStep (i) is from about 10° C. to about 160° C., the temperature in Step(ii) is from about −10° C. to about 160° C., the temperature in Step(iii) is from about 0° C. to about 70° C., the temperature in Step (iv)is from about 0° C. to about 70° C., and the temperature in Step (v) isfrom about 0° C. to about 70° C.
 13. A process according to claim 1,wherein in Step (i) a molar excess of 2-amino-(5-6-diethyl)-indan isused based on the amount of 8-substitutedoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one.
 14. A process according to claim1, wherein the salt having Formula (V) is5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-phenylmethoxy-(1H)-quinolin-2-onebenzoate.
 15. A process according to claim 1, wherein the 8-substitutedoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one of Formula (I) is prepared by thesteps comprising: (a) reacting an 8-(substitutedoxy)-5-haloacetyl-(1H)-quinolin-2-one with a reducing agent in thepresence of a chiral catalyst to form 8-(substitutedoxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one; and (b)treating the 8-(substitutedoxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one with a base inthe presence of a solvent to form 8-(substitutedoxy)-5-(R)-oxiranyl-(1H)-quinolin-2-one.
 16. A process according toclaim 15 wherein in Step (a) the 8-substitutedoxy-5-haloacetyl-(1H)-quinolin-2-one is reacted with a borane reagent inthe presence of a oxazaborolidine chiral catalyst.
 17. A processaccording to claim 16 wherein the borane reagent is selected from thegroup consisting of borane-tetrahydrofuran, borane-N,N-diethylanilineand borane-methyl sulphide, and the chiral catalyst is(R)-tetrahydro-1-methyl-3,3-diphenyl-(1H,3H)-pyrrolo[1,2-c][1,3,2]-oxazaborole.18. A process according to claim 15 wherein the temperature in Step (a)is from about −10° C. to about 80° C., and the temperature in Step (b)is from about 30° C. to about 80° C.
 19. A process for preparing5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt or an acceptable solvate thereof comprising: (a) reacting an8-(substituted oxy)-5-haloacetyl-(1H)-quinolin-2-one with a reducingagent in the presence of a chiral catalyst to form 8-(substitutedoxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one; (b) treatingthe 8-(substitutedoxy)-5-((R)-2-halo-1-hydroxy-ethyl)-(1H)-quinolin-2-one with a base inthe presence of a solvent to form 8-(substitutedoxy)-5-(R)-oxiranyl-(1H)-quinolin-2-one; (c) reacting the 8-substitutedoxy-5-(R)-oxiranyl-(1H)-quinolin-2-one having Formula (I)

with 2-amino-(5-6-diethyl)-indan to form a reaction mixture containingcompounds having Formulae (II), (III) and (IV)

wherein R is a protecting group; (d) treating the reaction mixtureprepared in Step (i) with an acid in the presence of a solvent to form acorresponding salt; (e) isolating and crystallizing a salt havingFormula (V)

wherein R is a protecting group and A⁻ is an anion; f) removing theprotecting group from the salt having Formula (V) in the presence of asolvent to form a salt having Formula (VI):

wherein A⁻ is an anion; and (g) treating the salt having Formula (VI)with an acid in the presence of a solvent to form a5-[(R)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1H)-quinolin-2-onesalt having Formula (VII)

wherein X⁻ is an anion.
 20. A compound having Formula (VIII)

wherein R is a protecting group.
 21. A compound having Formula (IX)


22. A compound having Formula (X)